The amphiphilicity and detergent properties of a substance, such as of a drug, correlate to their adsorption in the gastro-intestinal tract, to their distribution in the tissues and especially to their blood-brain barrier (BBB) permeability, liver metabolism, and urinary excretion, that is to their so-called ADME properties. One way to estimate molecular hydrophobocity is to determine the partition coefficient (log P) of the substance in octanol/water. Amphiphilicity and detergent properties have conventionally been determined by measuring the effect of the substance on the surface tension of water. The surface tension can be measured in a variety of ways, for example, in a method involving the use of a Wilhelmy plate or a du Nouy ring.
A problem relating to a majority of the substances to be used for pharmaceutical purposes and thus to be tested for their ADME properties is their poor solubility in water. For this reason, the pharmaceutical industry routinely uses a so-called base solution of the drug, which is a solution of the drug in dimethylsulfoxide (DMSO), the solution being 10 mM with respect to the drug. However, DMSO is not well suited for the use in surface tension measurements because its surface tension is low and it lowers the surface tension of water and of aqueous solutions. The 10 mM solutions of the drug in DMSO are used in undiluted form, because the changes in surface tension brought about by the substances from which the ADME properties can be evaluated, require the concentration to be varied on a micro-millimolar scale. The DMSO carried over into the system significantly reduces the signal obtained, that is the sensitivity of measurement.
Poor pharmacokinetics is currently the major reason for the failure of compounds in clinical trials. Accordingly, there is an urgent need for easy, high-throughput, and robust screening methods for pharmacokinetics. A procedure for the estimation of BBB-permeability based on the surface activity of drugs has recently been suggested (Seelig, R. et al.: A method to determine the ability of drugs to diffuse through the blood-brain barrier, Proc. Natl. Acad. Sci. USA 91:68-72 (1994); Fischer H. et al., Blood-brain barrier permeation: molecular parameters governing passive diffusion, J. Membrane Biol. 165:201-211 (1998)). However, although the predictive value of the method is excellent, the method described by these authors is slow, the measurement cycle approaching maximally four hours. Moreover, due to the large cuvette volumes needed, the consumption of compounds is high.
The present invention alleviates the disadvantages associated with the known method and provides a sensitive method for measuring the surface tension. The method allows for the screening of compounds with excellent prediction, for example, of BBB-permeability of compounds entering the central nervous system by passive diffusion. The data obtained also reveal a good correlation to the urinary excretion of the drugs, thus pointing out the common biophysical nature of some of the pharmacokinetic determinants in ADME.